Hydrogen-Associated CXCL2 Drives Adaptive Inflammatory-to-Proliferative State Transition during Skin Wound Healing

Abstract Background Wound healing is an environmentally adaptive process. It requires a tightly coordinated transition from an inflammatory to a proliferative state, which occurs in response to oxidative and inflammatory stress. Molecular hydrogen (H2) is a widely recognized medical gas, and it alleviates oxidative stress and selectively eliminates highly cytotoxic reactive oxygen species. However, it remains unclear whether redox-active gases such as H2 can actively orchestrate tissue state transitions, rather than merely mitigating oxidative damage. Methods Bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomic analyses were integrated to investigate the cellular and molecular mechanisms underlying H2-mediated wound healing. Functional studies were performed in hydrogen-mediated mouse skin injury models and in self-assembled skin organoid models. Immunofluorescence staining, Masson’s trichrome staining, and qRT-PCR were used to validate key signaling pathways and assess tissue regeneration, angiogenesis, and wound healing outcomes. Results H2 significantly accelerated wound healing, especially during the proliferative phase, where it acted as a critical regulator of the inflammatory-to-proliferative transition. Multi-omics analyses identified a hydrogen-associated macrophage program and revealed a CXCL2-ACKR1 signaling axis mediating macrophage-endothelial communication. Functional validation confirmed that activation of this axis promoted endothelial migration, angiogenesis, and granulation tissue formation. As a result, the transition from inflammation to proliferation was facilitated, and wound closure was accelerated. Conclusions H2 spatiotemporally coordinates adaptive wound healing by regulating a macrophage-endothelial CXCL2-ACKR1 signaling axis that drives the inflammatory-to-proliferative transition. These findings provide mechanistic insight into how H2 spatiotemporally coordinates adaptive wound healing and highlight the potential of hydrogen-mediated redox modulation as a mechanism for regulating tissue repair.